Nucleophilic imidazole ring nitrogen

Serine itself would be insufficiently nucleophilic to attack the ester carbonyl, so the reaction is facilitated by participation of the imidazole ring of histidine. The basic nitrogen in this residue is oriented so that it can remove a proton from the serine hydroxyl, increasing nucleophilicity and allowing attack on the ester carbonyl. This leads to formation of the transient acetylated enzyme, and release of choline. Hydrolysis of the acetylated enzyme utilizes water as nucleophile, but again involves the imidazole ring, and regenerates the free enzyme. 

Nucleophilic reactions of this type are a result of the weakly acidic nature of the pyrrole-type nitrogen in the imidazole ring. These acidic properties are slightly more pronounced than those of pyrrole... 

Imidazole (1) can be considered as having properties similar to both P3nrole and pyridine. In consequence, one would expect that electrophilic reagents would attack the unshared electron pair on N-3, but not that on the pyrrole nitrogen since it is part of the aromatic sextet. The ring carbons, too, are prone to attack by electrophilic, radical and nucleophilic species to a greater or lesser extent substitution reactions which do not destroy the aromatic character are predominant. While the imidazole ring is rather susceptible to electrophilic attack on an annular carbon, it is much less likely to become involved in nucleophilic... 

N-Aryl substituents usually depress the basic properties of the imidazole or benzimidazole nucleus. The effects of substituents on the aryl group are evident from the data listed in Table 7 which also lists rate constants for quaternization with iodoethane, a reaction which is dependent upon the nucleophilic character of the pyridine-type nitrogen (70CHE194). A phenyl group withdraws electrons from the imidazole ring, but does so rather weakly. The p value of +0.753 for the protonation process is in accord with weak electron transfer from the phenyl substituent to the basic nitrogen. 

The other nitrogen nucleophile available to enzymes is the versatile imidazole ring of histidine. This group is used more often for acid/base chemistry, but it is used occasionally as a nucleophile in, for example, phosphotransfer reactions. The serine proteases, such as a-chymotrypsin, which is illustrated in Figs. 2a and (2)b, are classic examples of the participation of serine as a nucleophile. Additional examples exist of nucleophilic mechanisms that employ the hydroxyl groups of threonine and tyrosine and the carboxylate groups of aspartate and glutamate. 

The product of this reaction, formylglycinamidine ribonucleotide, cyclizes to form the five-membered imidazole ring found in purines. Although this cyclization is likely to be favorable thermodynamically, a molecule of ATP is consumed to ensure irreversibility. The familiar pattern is repeated a phosphoryl group from the ATP molecule activates the carbonyl group and is displaced by the nitrogen atom attached to the ribose molecule. Cyclization is thus an intramolecular reaction in which the nucleophile and phosphate-activated carbon atom are present within the same molecule. 

Comprehensive compilations of pK data for imidazoles have appeared and more recent data have been collected in Table 1,1 8.173 isi jjjg nucleophilic (or basic) nature of the multiply bonded ring nitrogen of imidazole... 

A C—N bond is formed during nucleophilic attack by a pyridine-type nitrogen on an cu-haloethylamine side-chain [2663]. When an even weaker base is used in this type of cyclization, a partly reduced imidazole ring is formed [2310]. If other easily displaced halogen atoms are present, ring closure with sodium sulphide or an alkylamine may be accompanied by displacement of the second halogen... 

Intramolecular catalysis of ester hydrolysis by nitrogen nucleophiles is also important. The role of imidazole rings in intramolecular catalysis has received particularly close scruhny. There are two reasons for this. One is that the imidazole ring of... 

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